Bicyclic heterocyclic compounds pharmaceutical compositions containing these compounds, their use and process for preparing the same

ABSTRACT

The present invention relates methods for treating disease conditions selected from the list consisting of benign or malignant tumors, diseases of the airways and lungs, diseases of the gastrointestinal tract, the bile duct and the gall bladder by administration to a patient in need thereof of a therapeutically effective amount of a bicyclic heterocyclic groups of general formula 
     
       
         
         
             
             
         
       
     
     wherein said substituents are as defined herein.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 12/072,510, filed Feb. 26, 2008, which is a continuation of U.S.Application Ser. No. 11/497,727, filed Aug. 2, 2006, which is acontinuation of U.S. application Ser. No. 11/083,247, filed Mar. 17,2005 which is a divisional application of U.S. application Ser. No.10/400,370 benefit of which is claimed under 35 U.S.C. §121 and ishereby incorporated by reference.

FIELD OF INVENTION

This invention relates to bicyclic heterocyclic compounds active asinhibitors of signal transduction mediated by tyrosine kinases. Theinvention also relates to processes for preparing such compounds andpharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

Inhibitors of signal transduction mediated by tyrosine kinases useful inthe treatment of tumoral diseases as well as benign prostate hyperplasia(BPH) diseases of the lungs and respiratory tract. Tyrosine kinaseinhibitors have been reported for the treatment of hyper-secretoryrespitory diseases. WO 00/10588.

SUMMARY AND DESCRIPTION OF THE INVENTION

The present invention relates to bicyclic heterocyclic groups of generalformula

the tautomers, the stereoisomers, the mixtures and the salts thereof,particularly the physiologically acceptable salts thereof with inorganicor organic acids or bases which have valuable pharmacologicalproperties, particularly an inhibitory effect on signal transductionmediated by tyrosine kinases, the use thereof for treating diseases,particularly tumoral diseases, as well as benign prostate hyperplasia(BPH), diseases of the lungs and respiratory tract, and the preparationthereof.

In the above general formula I

R^(a) denotes a hydrogen atom or a C₁₋₄-alkyl group,R^(b) denotes a phenyl or 1-phenylethyl group, wherein the phenylnucleus is substituted in each case by the groups R¹ to R³, while

-   -   R¹ and R², which may be identical or different, in each case        denote a hydrogen, fluorine, chlorine, bromine or iodine atom,    -   a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, C₂₋₃-alkenyl or C₂₋₃-alkynyl        group,    -   an aryl, aryloxy, arylmethyl or arylmethoxy group,    -   a heteroaryl, heteroaryloxy, heteroarylmethyl or        heteroarylmethoxy group,    -   a methyl or methoxy group substituted by 1 to 3 fluorine atoms        or    -   a cyano, nitro or amino group, and    -   R³ denotes a hydrogen, fluorine, chlorine or bromine atom or    -   a methyl or trifluoromethyl group,        R^(c) denotes a cyclobutyl, cyclopentyl or cyclohexyl group        which is substituted in each case by a group R⁴—N—R⁵, while    -   R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group and    -   R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,    -   an aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-ylcarbonyl-C₁₋₃-alkyl,        piperidin-1-ylcarbonyl-C₁₋₃-alkyl,        homopiperidin-1-ylcarbonyl-C₁₋₃-alkyl,        morpholin-4-ylcarbonyl-C₁₋₃-alkyl,        homomorpholin-4-ylcarbonyl-C₁₋₃-alkyl,        piperazin-1-ylcarbonyl-C₁₋₃-alkyl,        4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl-C₁₋₃-alkyl,        homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl or a        4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl group,    -   a hydroxy-C₂₋₄-alkyl, C₁₋₃-alkyloxy-C₂₋₄-alkyl,        C₁₋₄-alkyloxy-carbonylamino-C₂₋₄-alkyl, amino-C₂₋₄-alkyl,        C₁₋₃-alkylamino-C₂₋₄-alkyl, di-(C₁₋₃-alkyl)amino-C₂₋₄-alkyl,        C₁₋₃-alkylcarbonylamino-C₂₋₄-alkyl,        aminocarbonylamino-C₂₋₄-alkyl,        C₁₋₃-alkylaminocarbonylamino-C₂₋₄-alkyl,        di-(C₁₋₃-alkyl)amino-carbonylamino-C₂₋₄-alkyl,        pyrrolidin-1-ylcarbonylamino-C₂₋₄-alkyl,        piperidin-1-ylcarbonylamino-C₂₋₄-alkyl,        morpholin-4-ylcarbonylamino-C₂₋₄-alkyl,        C₁₋₃-alkylsulphonyl-C₂₋₄-alkyl or a        C₁₋₃-alkylsulphonylamino-C₂₋₄-alkyl group,    -   a (2-oxo-pyrrolidin-1-yl)-C₂₋₄-alkyl,        (2-oxopiperidin-1-yl)-C₂₋₄-alkyl,        (3-oxo-morpholin-4-yl)-C₂₋₄-alkyl,        (2-oxo-imidazolidin-1-yl)-C₂₋₄-alkyl,        (2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl)-C₂₋₄-alkyl,        (2-oxo-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl or a        (2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl group,    -   a C₁₋₄-alkylsulphonyl, chloro-C₁₋₄-alkylsulphonyl,        bromo-C₁₋₄-alkylsulphonyl, amino-C₁₋₄-alkylsulphonyl,        C₁₋₃-alkylamino-C₁₋₄-alkylsulphonyl,        di-(C₁₋₃-alkyl)amino-C₁₋₄-alkylsulphonyl,        (pyrrolidin-1-yl)-C₁₋₄-alkylsulphonyl,        (piperidin-1-yl)-C₁₋₄-alkylsulphonyl,        (homopiperidin-1-yl)-C₁₋₄-alkylsulphonyl,        (morpholin-4-yl)-C₁₋₄-alkylsulphonyl,        (homomorpholin-4-yl)-C₁₋₄-alkylsulphonyl,        (piperazin-1-yl)-C₁₋₄-alkylsulphonyl,        (4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkylsulphonyl,        (homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl or a        (4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl group,    -   a C₁₋₄-alkyloxycarbonyl group,    -   a formyl, C₁₋₄-alkyl-carbonyl,        C₁₋₃-alkyloxy-C₁₋₄-alkyl-carbonyl, tetrahydrofuranylcarbonyl,        tetrahydropyranylcarbonyl, amino-C₁₋₄-alkyl-carbonyl,        C₁₋₃-alkylamino-C₁₋₄-alkyl-carbonyl,        di-(C₁₋₃-alkyl)amino-C₁₋₄-alkyl-carbonyl,        pyrrolidin-1-yl-C₁₋₄-alkyl-carbonyl,        piperidin-1-yl-C₁₋₄-alkyl-carbonyl,        (homopiperidin-1-yl)-C₁₋₄-alkyl-carbonyl,        morpholin-4-yl-C₁₋₄-alkyl-carbonyl,        (homomorpholin-4-yl)-C₁₋₄-alkyl-carbonyl,        (piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,        (4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,        (homopiperazin-1-yl)-C₁₋₄-alkyl-carbonyl,        (4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkyl-carbonyl or a        C₁₋₃-alkylsulphonyl-C₁₋₄-alkyl-carbonyl group,    -   a cyano, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)amino-carbonyl,        (C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,        N—(C₁₋₃-alkyl)-N—(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,        arylaminocarbonyl, pyrrolidin-1-ylcarbonyl,        piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl,        morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl,        2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,        piperazin-1-ylcarbonyl, 4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl,        homopiperazin-1-ylcarbonyl,        4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl, aminosulphonyl,        C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)amino-sulphonyl,        pyrrolidin-1-yl-sulphonyl, piperidin-1-ylsulphonyl,        homopiperidin-1-ylsulphonyl, morpholin-4-ylsulphonyl,        homomorpholin-4-ylsulphonyl, piperazin-1-ylsulphonyl,        4-C₁₋₃-alkyl-piperazin-1-ylsulphonyl,        homopiperazin-1-ylsulphonyl or a        4-C₁₋₃-alkyl-homopiperazin-1-ylsulphonyl group,        a cyclobutyl, cyclopentyl or cyclohexyl group which is        substituted in each case by a group R⁶, where    -   R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,        3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,        2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl,        2-oxo-hexahydropyrimidin-1-yl or a        2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl group,        an azetidin-3-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        a pyrrolidin-3-yl group which is substituted in the 1 position        by the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-3-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-4-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or        tetrahydropyran-4-yl group,        R^(d) denotes a hydrogen atom or a fluorine, chlorine or bromine        atom,        a hydroxy group,        a C₁₋₄-alkyloxy group,        a methoxy group substituted by 1 to 3 fluorine atoms,        an ethyloxy group substituted by 1 to 5 fluorine atoms,        a C₂₋₄-alkyloxy group which is substituted by a group R⁶ or R⁷,        while    -   R⁶ is as hereinbefore defined and    -   R⁷ denotes a hydroxy, C₁₋₃-alkyloxy, C₃₋₆-cycloalkyloxy, amino,        C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino,        bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl,        homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,        2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,        4-C₁₋₃-alkyl-piperazin-1-yl, homopiperazin-1-yl or        C₁₋₃-alkyl-homopiperazin-1-yl group, or    -   a formylamino, C₁₋₄-alkylcarbonylamino,        C₁₋₃-alkyloxy-C₁₋₃-alkylcarbonylamino,        C₁₋₄-alkyloxycarbonylamino, aminocarbonylamino,        C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,        piperazin-1-ylcarbonylamino,        4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino,        morpholin-4-ylcarbonylamino or a C₁₋₄-alkylsulphonylamino group,        a C₃₋₇-cycloalkyloxy or C₃₋₇-cycloalkyl-C₁₋₄-alkyloxy group,        a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or        tetrahydropyran-4-yloxy group,        a tetrahydrofuranyl-C₁₋₄-alkyloxy or        tetrahydropyranyl-C₁₋₄-alkyloxy group,        a C₁₋₄-alkoxy group which is substituted by a pyrrolidinyl,        piperidinyl or homopiperidinyl group substituted in the 1        position by the group R⁸, while    -   R⁸ denotes a hydrogen atom or a C₁₋₃-alkyl group,        or a C₁₋₄-alkoxy group which is substituted by a morpholinyl        group substituted in the 4 position by the group R⁸, while R⁸ is        as hereinbefore defined, and        X denotes a methyne group substituted by a cyano group or a        nitrogen atom, and        by the aryl groups mentioned in the definition of the above        groups is meant in each case a phenyl group which is mono- or        disubstituted by R⁹, while the substituents may be identical or        different and    -   R⁹ denotes a hydrogen atom, a fluorine, chlorine, bromine or        iodine atom or a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy,        difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy or cyano group,        by the heteroaryl groups mentioned in the definition of the        above groups is meant a pyridyl, pyridazinyl, pyrimidinyl or        pyrazinyl group, while the above-mentioned heteroaryl groups are        each mono- or disubstituted by the group R⁹, while the        substituents may be identical or different and R⁹ is as        hereinbefore defined, and        the abovementioned pyrrolidinyl, piperidinyl, piperazinyl and        morpholinyl groups may be substituted in each case by one or two        C₁₋₃-alkyl groups, and        unless otherwise stated, the abovementioned alkyl groups may be        straight-chained or branched,        with the proviso that the compound        4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline        is excluded.

Preferred compounds of the above general formula I are those wherein

R^(a) denotes a hydrogen atom,R^(b) denotes a phenyl group substituted by the groups R¹ to R³, while

-   -   R¹ denotes a hydrogen, fluorine, chlorine or bromine atom,    -   a methyl, trifluoromethyl or ethynyl group,    -   a phenyloxy or phenylmethoxy group, while the phenyl moiety of        the abovementioned groups is optionally substituted by a        fluorine or chlorine atom, or    -   a pyridyloxy or pyridinylmethoxy group, while the pyridinyl        moiety of the abovementioned groups is optionally substituted by        a methyl or trifluoromethyl group,    -   R² denotes a hydrogen, fluorine or chlorine atom or a methyl        group and    -   R³ denotes a hydrogen atom,        R^(c) denotes a cyclopentyl group which is substituted in the 3        position by a group R⁴—N—R⁵, while    -   R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group and    -   R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,    -   an aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,        di-(C₁₋₃-alkyl)aminocarbonyl-C₁₋₃-alkyl,        pyrrolidin-1-ylcarbonyl-C₁₋₃-alkyl,        piperidin-1-ylcarbonyl-C₁₋₃-alkyl,        piperazin-1-ylcarbonyl-C₁₋₃-alkyl,        4-C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl or        morpholin-4-ylcarbonyl-C₁₋₃-alkyl group,    -   a hydroxy-C₂₋₄-alkyl, C₁₋₃-alkyloxy-C₂₋₄-alkyl,        C₁₋₄-alkyloxy-carbonylamino-C₂₋₄-alkyl, amino-C₂₋₄-alkyl,        C₁₋₃-alkylamino-C₂₋₄-alkyl, di-(C₁₋₃-alkyl)amino-C₂₋₄-alkyl,        C₁₋₃-alkylcarbonylamino-C₂₋₄-alkyl,        aminocarbonylamino-C₂₋₄-alkyl,        C₁₋₃-alkylaminocarbonylamino-C₂₋₄-alkyl,        di-(C₁₋₃-alkyl)aminocarbonylamino-C₂₋₄-alkyl,        morpholin-4-ylcarbonylamino-C₂₋₄-alkyl,        C₁₋₃-alkylsulphonyl-C₂₋₄-alkyl or        C₁₋₃-alkylsulphonylamino-C₂₋₄-alkyl group,    -   a (2-oxo-pyrrolidin-1-yl)-C₂₋₄-alkyl,        (2-oxopiperidin-1-yl)-C₂₋₄-alkyl,        (3-oxo-morpholin-4-yl)-C₂₋₄-alkyl,        (2-oxo-imidazolidin-1-yl)-C₂₋₄-alkyl,        (2-oxo-3-methyl-imidazolidin-1-yl)-C₂₋₄-alkyl,        (2-oxo-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl or        (2-oxo-3-methyl-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl group,    -   a C₁₋₃-alkylsulphonyl, chloro-C₂₋₄-alkylsulphonyl,        bromo-C₂₋₄-alkylsulphonyl, amino-C₂₋₄-alkylsulphonyl,        C₁₋₃-alkylamino-C₂₋₄-alkylsulphonyl,        di-(C₁₋₃-alkyl)amino-C₂₋₄-alkylsulphonyl,        (pyrrolidin-1-yl)-C₂₋₄-alkylsulphonyl,        (piperidin-1-yl)-C₂₋₄-alkylsulphonyl or        (morpholin-4-yl)-C₂₋₄-alkylsulphonyl group,    -   a C₁₋₄-alkyloxy-carbonyl group,    -   a formyl, C₁₋₃-alkyl-carbonyl,        C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonyl, tetrahydrofuranylcarbonyl,        tetrahydropyranylcarbonyl, amino-C₁₋₃-alkyl-carbonyl,        C₁₋₃-alkylamino-C₁₋₃-alkyl-carbonyl,        di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyl-carbonyl,        pyrrolidin-1-yl-C₁₋₃-alkyl-carbonyl,        piperidin-1-yl-C₁₋₃-alkyl-carbonyl,        piperazin-1-yl-C₁₋₃-alkyl-carbonyl,        4-C₁₋₃-alkyl-piperazin-1-yl-C₁₋₃-alkyl-carbonyl,        morpholin-4-yl-C₁₋₃-alkyl-carbonyl or a        C₁₋₃-alkylsulphonyl-C₁₋₃-alkyl-carbonyl group,    -   a cyano, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,        di-(C₁₋₃-alkyl)amino-carbonyl,        (C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,        N—(C₁₋₃-alkyl)-N—(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,        phenylaminocarbonyl, pyrrolidin-1-ylcarbonyl,        piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,        C₁₋₃-alkyl-morpholin-4-ylcarbonyl,        di-(C₁₋₃-alkyl)morpholin-4-ylcarbonyl,        homomorpholin-4-ylcarbonyl,        2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,        piperazin-1-ylcarbonyl, 4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl,        aminosulphonyl, C₁₋₃-alkyl-aminosulphonyl,        di-(C₁₋₃-alkyl)amino-sulphonyl, pyrrolidin-1-yl-sulphonyl,        piperidin-1-ylsulphonyl or a morpholin-4-ylsulphonyl group, or        a cyclopentyl group which is substituted in the 3 position by a        group R⁶, while    -   R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,        3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,        2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl        or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,        a cyclohexyl group which is substituted in the 3 position or in        the 4 position by a group R⁴—N—R⁵, while R⁴ and R⁵ are as        hereinbefore defined,        a cyclohexyl group which is substituted in the 3 position or in        the 4 position by a group R⁶, while R⁶ is as hereinbefore        defined,        a pyrrolidin-3-yl group which is substituted in the 1 position        by the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-3-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-4-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined, or        a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or        tetrahydropyran-4-yl group,        R^(d) denotes a hydrogen atom,        a C₁₋₃-alkyloxy group,        a methoxy group which is substituted by one to three fluorine        atoms,        an ethyloxy group which is substituted in the 2 position by a        group R⁶ or R⁷, while R⁶ is as hereinbefore defined and    -   R⁷ denotes a hydroxy, C₁₋₃-alkyloxy, amino, C₁₋₃-alkylamino,        di-(C₁₋₃-alkyl)amino, bis-(2-methoxyethyl)-amino,        pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,        homomorpholin-4-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl or a        4-C₁₋₃-alkyl-piperazin-1-yl group, or    -   a formylamino, C₁₋₄-alkylcarbonylamino,        C₁₋₃-alkyloxy-C₁₋₃-alkylcarbonylamino,        C₁₋₄-alkyloxycarbonylamino, aminocarbonylamino,        C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,        pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,        piperazin-1-ylcarbonylamino,        4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino-morpholin-4-ylcarbonylamino        or a C₁₋₄-alkylsulphonylamino group,        a propyloxy group which is substituted in the 3 position by a        group R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, or        a butyloxy group which is substituted in the 4 position by a        group R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, and        X denotes a nitrogen atom,        while, unless stated otherwise, the abovementioned alkyl groups        may be straight-chained or branched,        their tautomers, their stereoisomers, their mixtures and their        salts.

Particularly preferred compounds of the above general formula I arethose wherein

R^(a) denotes a hydrogen atom,R^(b) denotes a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or3-chloro-4-fluoro-phenyl group,a 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl,4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-methyl-4-(pyridin-3-yloxy)-phenyl,3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-chloro-4-(pyridin-3-yloxy)-phenyl or3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,R^(c) denotes a cyclohexyl group which is substituted in the 3 positionor in the 4 position by a group R⁴—N—R⁵, while

-   -   R⁴ denotes a hydrogen atom, a methyl or ethyl group and    -   R⁵ denotes a hydrogen atom, a methyl, aminocarbonylmethyl,        methylamino-carbonylmethyl, dimethylaminocarbonylmethyl,        pyrrolidin-1-ylcarbonylmethyl, piperidin-1-ylcarbonylmethyl,        piperazin-1-ylcarbonylmethyl,        4-methylpiperazin-1-ylcarbonylmethyl,        morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl-carbonyl)ethyl        or 3-(morpholin-4-yl-carbonyl)propyl group,    -   an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl,        2-methoxyethyl, 3-methoxypropyl,        2-(butyloxycarbonylamino)-ethyl, 2-aminoethyl, 3-aminopropyl,        2-(acetylamino)ethyl, 3-(acetylamino)propyl,        2-(ethylcarbonylamino)ethyl, 3-(ethylcarbonylamino)propyl,        2-(propylcarbonylamino)ethyl, 3-(propylcarbonylamino)propyl,        2-(ethylaminocarbonylamino)ethyl,        3-(ethylaminocarbonylamino)propyl,        2-(dimethylaminocarbonylamino)ethyl,        3-(dimethylaminocarbonylamino)propyl,        2-(morpholin-4-ylcarbonylamino)ethyl,        3-(morpholin-4-ylcarbonylamino)propyl, 2-(methylsulphonyl)ethyl,        3-(methylsulphonyl)propyl, 2-(methylsulphonyl-amino)ethyl or a        3-(methylsulphonylamino)propyl group,    -   a 2-(2-oxo-pyrrolidin-1-yl)ethyl, 2-(2-oxopiperidin-1-yl)ethyl,        2-(3-oxo-morpholin-4-yl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,        2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl,        2-(2-oxo-hexahydropyrimidin-1-yl)ethyl or a        2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl group,    -   a 3-(2-oxo-pyrrolidin-1-yl)propyl,        3-(2-oxopiperidin-1-yl)propyl, 3-(3-oxo-morpholin-4-yl)propyl,        3-(2-oxo-imidazolidin-1-yl)propyl,        3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl,        3-(2-oxo-hexahydropyrimidin-1-yl)propyl or a        3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl group,    -   a methylsulphonyl, ethylsulphonyl, 3-chloropropylsulphonyl,        2-(morpholin-4-yl)-ethylsulphonyl or a        3-(morpholin-4-yl)-propylsulphonyl group,    -   a propyloxycarbonyl or butyloxycarbonyl group,    -   a formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxyacetyl,        (2-methoxyethyl)carbonyl, (3-methoxypropyl)carbonyl,        tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl,        aminoacetyl, methylaminoacetyl, dimethylaminoacetyl,        morpholin-4-ylacetyl, [2-(morpholin-4-yl)ethyl]carbonyl,        [3-(morpholin-4-yl)propyl]carbonyl or a methylsulphonylacetyl        group,    -   a cyano, aminocarbonyl, methylaminocarbonyl,        dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl,        propylaminocarbonyl, (2-methoxyethyl)aminocarbonyl,        N-methyl-N-(2-methoxyethyl)-aminocarbonyl,        (3-methoxypropyl)aminocarbonyl,        N-methyl-N-(3-methoxypropyl)-aminocarbonyl, phenylaminocarbonyl,        pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,        morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl,        2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl,        2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,        4-methylpiperazin-1-ylcarbonyl, aminosulphonyl,        methylaminosulphonyl, dimethylaminosulphonyl or a        morpholin-4-ylsulphonyl group,        a cyclohexyl group which is substituted in the 3 position or in        the 4 position by a group R⁶, while    -   R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,        3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,        2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl        or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,        a pyrrolidin-3-yl group which is substituted in the 1 position        by the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-3-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        a piperidin-4-yl group which is substituted in the 1 position by        the group R⁵, while R⁵ is as hereinbefore defined,        a tetrahydrofuran-3-yl, tetrahydropyran-3-yl or        tetrahydropyran-4-yl group,        R^(d) denotes a hydrogen atom,        a methoxy, difluoromethoxy or ethyloxy group,        an ethyloxy group which is substituted in the 2 position by a        group R⁶ or R⁷, while R⁶ is as hereinbefore defined and    -   R⁷ denotes a hydroxy, methoxy, ethoxy, amino, dimethylamino,        diethylamino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl,        piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,        2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,        3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,        8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,        4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl group, or    -   an acetylamino, ethylcarbonylamino, propylcarbonylamino,        butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino,        ethylaminocarbonylamino, dimethylaminocarbonylamino,        pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,        morpholin-4-ylcarbonylamino, methylsulphonylamino,        ethylsulphonylamino or butylsulphonylamino group,        a propyloxy group which is substituted in the 3 position by a        group R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, or        a butyloxy group which is substituted in the 4 position by a        group R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, and        X denotes a nitrogen atom,        while, unless stated otherwise, the abovementioned alkyl groups        may be straight-chained or branched,        their tautomers, their stereoisomers, their mixtures and their        salts.

Most particularly preferred compounds of general formula I are thosewherein

R^(a) denotes a hydrogen atom,R^(b) denotes a 3-bromophenyl, 3,4-difluorophenyl,3-chloro-4-fluoro-phenyl or a 3-ethynylphenyl group, ora 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluorbenzyl)oxy]-phenyl,4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-methyl-4-(pyridin-3-yloxy)-phenyl,3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-chloro-4-(pyridin-3-yloxy)-phenyl or3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,R^(c) denotes a cyclohexyl group which is substituted in the 3 positionby an amino, acetylamino, tert.-butyloxycarbonylamino ormethylsulphonylamino group,a cyclohexyl group which is substituted in the 4 position by an amino,methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino,methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino,morpholin-4-ylcarbonylmethylamino,[3-(morpholin-4-ylcarbonyl)propyl]amino,[2-(methylsulphonyl)ethyl]amino, [3-(methylsulphonyl)propyl]amino or[2-(methylsulphonylamino)ethyl]amino group,a cyclohexyl group which is substituted in the 4 position by a[2-(2-oxo-pyrrolidin-1-yl)ethyl]amino,[2-(2-oxopiperidin-1-yl)ethyl]amino,[2-(2-oxo-imidazolidin-1-yl)ethyl]amino,[2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl]amino,[2-(2-oxo-hexahydropyrimidin-1-yl)ethyl]amino or[2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl]amino group,a cyclohexyl group which is substituted in the 4 position by a[3-(2-oxo-pyrrolidin-1-yl)propyl]amino,[3-(2-oxopiperidin-1-yl)propyl]amino,[3-(2-oxo-imidazolidin-1-yl)propyl]amino,[3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl]amino,[3-(2-oxo-hexahydropyrimidin-1-yl)propyl]amino or[3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl]amino group,a cyclohexyl group which is substituted in the 4 position by anacetylamino, N-(acetyl)-methylamino, aminomethylcarbonylamino,methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino,morpholin-4-ylmethylcarbonylamino, methoxyacetylamino,N-(methoxyacetyl)-methylamino, tetrahydropyran-4-ylcarbonylamino,N-(tetrahydropyran-4-ylcarbonyl)-methylamino,tert.-butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino,aminocarbonylamino, methylaminocarbonylamino,N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino,N-(dimethylaminocarbonyl)-methylamino,N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino,N-(morpholin-4-ylcarbonyl)-methylamino orN-(4-methylpiperazin-1-ylcarbonyl)-methylamino group,a cyclohexyl group which is substituted in the 4 position by a2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl,2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin-1-yl,2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-methyl-hexahydropyrimidin-1-yl group,a cyclohexyl group which is substituted in the 4 position by amethylsulphonylamino, N-(methylsulphonyl)-methylamino,ethylsulphonylamino, N-(ethylsulphonyl)-methylamino,dimethylaminosulphonylamino, N-(dimethylaminosulphonyl)-methylamino,morpholin-4-ylsulphonylamino,N-(morpholin-4-ylsulphonyl)-methylamino-3-chloropropylsulphonylamino,[2-(morpholin-4-yl)-ethyl]sulphonylamino or[3-(morpholin-4-yl)-propyl]sulphonylamino- group,a pyrrolidin-3-yl group,a pyrrolidin-3-yl group which is substituted in the 1 position by amethyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl,morpholin-4-ylcarbonyl or methylsulphonyl group,a piperidin-3-yl group,a piperidin-3-yl group which is substituted in the 1 position by amethyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl,morpholin-4-ylcarbonyl or methylsulphonyl group,a piperidin-4-yl group which is substituted in the 1 position by amethyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphonyl)-ethyl, 3-(methylsulphonyl)-propyl,2-(tert.-butyloxycarbonylamino)-ethyl, 2-aminoethyl,2-(acetylamino)-ethyl, 2-(ethylcarbonylamino)-ethyl,2-(propylcarbonylamino)-ethyl, 2-(ethylaminocarbonylamino)-ethyl,2-(dimethylaminocarbonylamino)-ethyl,2-(morpholin-4-ylcarbonylamino)-ethyl, 3-(acetylamino)-propyl,3-(ethylcarbonylamino)-propyl, 3-(propylcarbonylamino)-propyl,3-(ethylaminocarbonylamino)-propyl,3-(dimethylaminocarbonylamino)-propyl,3-(morpholin-4-ylcarbonylamino)-propyl, 2-(methylsulphonylamino)-ethyl,3-(methylsulphonylamino)-propyl, (aminocarbonyl)methyl,(methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl,(pyrrolidin-1-ylcarbonyl)methyl, (morpholin-4-ylcarbonyl)methyl,2-(morpholin-4-ylcarbonyl)-ethyl or 3-(morpholin-4-ylcarbonyl)-propylgroup,a piperidin-4-yl group which is substituted in the 1 position by a2-(2-oxo-pyrrolidin-1-yl)-ethyl, 2-(2-oxopiperidin-1-yl)-ethyl,2-(3-oxomorpholin-4-yl)-ethyl, 2-(2-oxo-imidazolidin-1-yl)-ethyl,2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl,2-(2-oxo-hexahydropyrimidin-1-yl)-ethyl or2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyl group,a piperidin-4-yl group which is substituted in the 1 position by a3-(2-oxo-pyrrolidin-1-yl)-propyl, 3-(2-oxopiperidin-1-yl)-propyl,3-(3-oxomorpholin-4-yl)-propyl, 3-(2-oxo-imidazolidin-1-yl)-propyl,3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyl,3-(2-oxo-hexahydropyrimidin-1-yl)-propyl or3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyl group,a piperidin-4-yl group which is substituted in the 1 position by aformyl, acetyl, methoxyacetyl, (2-methoxyethyl)carbonyl,(3-methoxypropyl)carbonyl, methylsulphonylacetyl, aminoacetyl,methylaminoacetyl, (dimethylamino)acetyl, (morpholin-4-yl)acetyl,[2-(morpholin-4-yl)-ethyl]carbonyl, [3-(morpholin-4-yl)-propyl]carbonyl,tetrahydrofuran-2-ylcarbonyl or tetrahydropyran-4-ylcarbonyl group,a piperidin-4-yl group which is substituted in the 1 position by acyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,(2-methoxyethyl)aminocarbonyl,N-methyl-N-(2-methoxyethyl)-aminocarbonyl,(3-methoxypropyl)aminocarbonyl,N-methyl-N-(3-methoxypropyl)-aminocarbonyl, isopropylaminocarbonyl,phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl,2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl ortert.-butyloxycarbonyl group,a piperidin-4-yl group which is substituted in the 1 position by amethylsulphonyl, ethylsulphonyl, [2-(morpholin-4-yl)-ethyl]sulphonyl,[3-(morpholin-4-yl)-propyl]sulphonyl, aminosulphonyl,methylaminosulphonyl, dimethylaminosulphonyl or morpholin-4-ylsulphonylgroup, ora tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-ylgroup,R^(d) denotes a hydrogen atom,a methoxy, difluoromethoxy or ethyloxy group,a 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or4-(morpholin-4-yl)butyloxy group,a 3-(dimethylamino)propyloxy, 3-(diethylamino)propyloxy,3-[bis-(2-methoxyethyl)-amino]propyloxy, 3-(piperazin-1-yl)propyloxy,3-(4-methylpiperazin-1-yl)propyloxy or3-(4-ethylpiperazin-1-yl)propyloxy group,a 3-(homomorpholin-4-yl)-propyloxy,3-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-propyloxy,3-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-propyloxy or3-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-propyloxy group,a 2-(2-oxo-pyrrolidin-1-yl)-ethyloxy, 2-(2-oxopiperidin-1-yl)-ethyloxy,2-(3-oxomorpholin-4-yl)-ethyloxy, 2-(2-oxo-imidazolidin-1-yl)-ethyloxy,2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyloxy,2-(2-oxo-hexahydropyrimidin-1-yl)-ethyloxy or2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyloxy group,a 3-(2-oxo-pyrrolidin-1-yl)-propyloxy,3-(2-oxopiperidin-1-yl)-propyloxy, 3-(3-oxomorpholin-4-yl)-propyloxy,3-(2-oxo-imidazolidin-1-yl)-propyloxy,3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyloxy,3-(2-oxo-hexahydropyrimidin-1-yl)-propyloxy or3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyloxy group,a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy,2-(amino)-ethyloxy, 2-(acetylamino)-ethyloxy,2-(ethylcarbonylamino)-ethyloxy, 2-(propylcarbonylamino)-ethyloxy,2-(isobutylcarbonylamino)-ethyloxy, 2-(methoxyacetylamino)-ethyloxy,2-(ethylaminocarbonylamino)-ethyloxy,2-(dimethylaminocarbonylamino)-ethyloxy,2-(pyrrolidin-1-ylcarbonylamino)-ethyloxy,2-(piperidin-1-ylcarbonylamino)-ethyloxy,2-(morpholin-4-ylcarbonylamino)-ethyloxy,2-(methylsulphonylamino)-ethyloxy group,2-(ethylsulphonylamino)-ethyloxy or 2-(butylsulphonylamino)-ethyloxygroup, ora 3-(tert.-butyloxycarbonylamino)-propyloxy, 3-(amino)-propyloxy,3-(acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group,andX denotes a nitrogen atom,their tautomers, their stereoisomers, their mixtures and their salts.

Particularly preferred compounds of general formula I are those wherein

R^(a) denotes a hydrogen atom,R^(b) preferably denotes a 3-chloro-4-fluoro-phenyl group or also a3-ethynylphenyl group,R^(c) denotes a cyclohexyl group which is substituted in the 3 positionby an amino, acetylamino, tert.-butyloxycarbonylamino ormethylsulphonylamino group,a cyclohexyl group which is substituted in the 4 position by an amino,methylamino, dimethylamino, acetylamino, N-(acetyl)-methylamino,methoxyacetylamino, N-(methoxyacetyl)-methylamino,tetrahydropyran-4-ylcarbonylamino,N-(tetrahydropyran-4-ylcarbonyl)-methylamino,tert.-butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino,N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino,N-(dimethylaminocarbonyl)-methylamino,N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino,N-(morpholin-4-ylcarbonyl)-methylamino,N-(4-methylpiperazin-1-ylcarbonyl)-methylamino, methylsulphonylamino,N-(methylsulphonyl)-methylamino, ethylsulphonylamino,N-(ethylsulphonyl)-methylamino, dimethylaminosulphonylamino,N-(dimethylaminosulphonyl)-methylamino, morpholin-4-ylsulphonylamino,N-(morpholin-4-ylsulphonyl)-methylamino, 3-chloropropylsulphonylamino,or [3-(morpholin-4-yl)-propyl]sulphonylamino group,a pyrrolidin-3-yl group,a pyrrolidin-3-yl group which is substituted in the 1 position by atert.-butyloxycarbonyl or methylsulphonyl group,a piperidin-3-yl group,a piperidin-3-yl group which is substituted in the 1 position by atert.-butyloxycarbonyl or methylsulphonyl group,a piperidin-4-yl group,a piperidin-4-yl group which is substituted in the 1 position by amethyl, (aminocarbonyl)methyl, (dimethylaminocarbonyl)methyl,(morpholin-4-ylcarbonyl)methyl, 2-(tert.-butyloxycarbonylamino)ethyl,2-aminoethyl, 2-(acetylamino)ethyl, 2-(methylsulphonylamino)ethyl,cyano, acetyl, methoxyacetyl, (dimethylamino)acetyl,(morpholin-4-yl)acetyl, tetrahydropyran-4-ylcarbonyl,ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl,dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl,isopropyloxycarbonyl, tert.-butyloxycarbonyl, methylsulphonyl,dimethylaminosulphonyl or morpholin-4-ylsulphonyl group, ora tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-ylgroup,R^(d) denotes a hydrogen atom,a methoxy or ethyloxy group,a 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or4-(morpholin-4-yl)butyloxy group,a 2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethyloxy group,a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy,2-amino-ethyloxy, 2-(acetylamino)-ethyloxy or2-(methylsulphonylamino)-ethyloxy group ora 3-(tert.-butyloxycarbonylamino)-propyloxy, 3-amino-propyloxy,3-(acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group,andX denotes a nitrogen atom,their tautomers, their stereoisomers, their mixtures and their salts.

Of the bicyclic heterocyclic groups of general formula I as describedabove as well as the sub-groups specified as being preferred,particularly preferred, most particularly preferred and especiallypreferred, special mention should be made of those compounds wherein

(a) R^(c) denotes a cyclohexyl group substituted in the 4 position,(b) R^(c) denotes a pyrrolidin-3-yl group optionally substituted in the1 position,(c) R^(c) denotes a piperidin-3-yl group optionally substituted in the 1position,(d) R^(c) denotes a piperidin-4-yl group optionally substituted in the 1position,(e) R^(c) denotes a tetrahydrofuran-3-yl group,(f) R^(c) denotes a tetrahydropyran-3-yl group, or(g) R^(c) denotes a tetrahydropyran-4-yl group,while R^(a), R^(b), R^(d) and X in each case are as hereinbeforedefined.

The following are mentioned as examples of particularly preferredcompounds of general formula I:

-   (1)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,-   (2)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline,-   (3)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,-   (4)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,-   (5)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,-   (6)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,-   (7)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   (8)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   (9)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,-   (10)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,-   (11)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,-   (12)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   (13)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   (14)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,-   (15)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulphonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,-   (16)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,-   (17)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   (18)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   (19)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,-   (20)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,-   (21)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline    and-   (22)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,    as well as their salts.

The compounds of general formula I may be prepared for example by thefollowing methods:

a) reacting a compound of general formula

whereinR^(a), R^(b), R^(d) and X are as hereinbefore defined, with a compoundof general formula

Z¹—R^(c),  (III)

whereinR^(c) is as hereinbefore defined and Z¹ denotes a leaving group such asa halogen atom, e.g. a chlorine or bromine atom, a sulphonyloxy groupsuch as a methanesulphonyloxy or p-toluenesulphonyloxy group or ahydroxy group.

With a compound of general formula III wherein Z¹ denotes a hydroxygroup, the reaction is carried out in the presence of a dehydratingagent, preferably in the presence of a phosphine and an azodicarboxylicacid derivative such as e.g. triphenylphosphine/diethylazodicarboxylate, conveniently in a solvent such as methylene chloride,acetonitrile, tetrahydrofuran, dioxane, toluene orethylenglycoldiethylether at temperatures between −50 and 150° C., butpreferably at temperatures between −20 and 80° C.

b) In order to prepare compounds of general formula I wherein R^(d)denotes one of the optionally substituted alkyloxy groups mentionedhereinbefore:reacting a compound of general formula

wherein R^(a), R^(b), R^(c) and X are as hereinbefore defined, with acompound of general formula

Z²—R^(d′),  (V)

wherein R^(d′), denotes a C₁₋₄-alkyl group, a methyl group substitutedby 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorineatoms, a C₂₋₄-alkyl group substituted by a group R⁶ or R⁷, where R⁶ andR⁷ are as hereinbefore defined, a C₁₋₄-alkyl group which is substitutedby a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted inthe 1 position by the group R⁸, or a C₁₋₄-alkyl group which issubstituted by a morpholinyl group substituted in the 4 position by thegroup R⁸, while R⁸ in each case is as hereinbefore defined, andZ² denotes a leaving group such as a halogen atom, an alkylsulphonyloxy,arylsulphonyloxy or a hydroxy group.

If the leaving group is a halogen atom such as a chlorine, bromine oriodine atom or an alkylsulphonyloxy or arylsulphonyloxy group such asthe methanesulphonyloxy or p-toluenesulphonyloxy group, the reaction ispreferably carried out in the presence of an organic or inorganic basesuch as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine.If the leaving group is a hydroxy group, the reaction is carried out inthe presence of a dehydrating agent, preferably in the presence of aphosphine and an azodicarboxylic acid derivative such as e.g.triphenylphosphine/diethyl azodicarboxylate.

c) In order to prepare compounds of general formula I wherein R^(d)denotes one of the abovementioned alkyloxy groups which is substitutedby an optionally substituted amino, alkylamino or dialkylamino group orby an optionally substituted heterocyclic group bound via animinonitrogen atom:reacting a compound of general formula

wherein R^(a), R^(b), R^(c) and X are as hereinbefore defined and Z³denotes a leaving group such as a halogen atom, e.g. a chlorine orbromine atom or a sulphonyloxy group such as a methanesulphonyloxy orp-toluenesulphonyloxy group,with ammonia, a corresponding, optionally substituted alkylamine,dialkylamine or an imino compound or the suitable salts or derivativesthereof, such as morpholine, for example.d) In order to prepare compounds of general formula I wherein R^(d)denotes a hydroxy group:Cleaving a protecting group from a compound of general formula

wherein R^(a), R^(b), R^(c) and X are as hereinbefore defined and R^(d″)denotes a group which may be converted into a hydroxy group, for examplean optionally substituted benzyloxy group, a trimethylsilyloxy,acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxy or trityloxy group.

The protecting group is cleaved for example by hydrolysis in an aqueoussolvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxan/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide or aprotically, e.g. in the presence of iodotrimethylsilane,at temperatures between 0 and 120° C., preferably at temperaturesbetween 10 and 100° C.

However, a benzyl or methoxybenzyl group is cleaved, for example,hydrogenolytically, e.g. with hydrogen in the presence of a catalystsuch as palladium/charcoal in a suitable solvent such as methanol,ethanol, ethyl acetate or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid at temperatures between 0and 100° C., but preferably at ambient temperatures between 20 and 60°C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.A 2,4-dimethoxybenzyl group, however, is preferably cleaved intri-fluoroacetic acid in the presence of anisole.

A tert.butyl or benzyl group is cleaved for example by treating with anacid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acidor by treating with iodotrimethylsilane, optionally using a solvent suchas methylene chloride, dioxan, methanol or diethyl ether.

e) In order to prepare compounds of general formula I wherein R^(c)contains a —NH— group:cleaving a protecting group from a compound of general formula

wherein R^(a), R^(b), R^(d) and X are as hereinbefore defined and R^(c′)has the meanings given for R^(c) hereinbefore, with the proviso thatR^(c) contains a protected nitrogen atom.

Conventional protecting groups for an amino, alkylamino or imino groupare for example the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl,tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group, while for the amino group the phthalyl groupis an additional possibility.

The protecting group is cleaved for example by hydrolysis in an aqueoussolvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxan/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide or aprotically, e.g. in the presence of iodotrimethylsilane,at temperatures between 0 and 120° C., preferably at temperaturesbetween 10 and 100° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas methylene chloride, dioxan, methanol or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid at temperatures between 50 and 120° C. or by treatingwith sodium hydroxide solution, optionally in the presence of a solventsuch as tetrahydrofuran at temperatures between 0 and 50° C.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

f) In order to prepare compounds of general formula I wherein R^(c)contains an alkyl group substituted by an optionally substituted amino,alkylamino or dialkyamino group or by an optionally substitutedheterocyclic group bound via a nitrogen atom:reacting a compound of general formula

wherein R^(a), R^(b), R^(d) and X are as hereinbefore defined, Z³denotes a leaving group, for example a halogen atom such as a chlorineor bromine atom, or a sulphonyloxy group such as a methanesulphonyloxyor p-toluenesulphonyloxy group, and R^(C″) has the meanings given forR^(c) hereinbefore with the proviso that a hydrogen atom bound to analiphatic carbon atom is replaced by the group Z³,with ammonia, a corresponding, optionally substituted alkylamine,dialkylamine or an imino compound or the appropriate salts orderivatives thereof, such as morpholine, for example.

If according to the invention a compound of general formula I isobtained which contains an amino, alkylamino or imino group, this may beconverted by acylation, cyanation or sulphonylation into a correspondingacyl, cyano or sulphonyl compound of general formula I, the acylatingagents being for example isocyanate, carbamoyl chloride, carboxylic acidhalide, carboxylic acid anhydride and carboxylic acids with activatingagents such as N,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimideor O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium-tetrafluoroborate,the sulphonylating agents being sulphonyl halides and the cyanatingagents being chlorine or bromocyanogen, and/or

if a compound of general formula I is obtained which contains an amino,alkylamino or imino group, this may be converted by alkylation orreductive alkylation into a corresponding alkyl compound of generalformula I and/orif a compound of general formula I is obtained which contains achloro-C₁₋₄-alkylsulphonyl or bromo-C₁₋₄-alkylsulphonyl group, this maybe converted by reaction with an amine into a correspondingamino-C₁₋₄-alkylsulphonyl compound and/orif a compound of general formula I is obtained which contains atert.-butyloxycarbonylamino, N-alkyl-N-(tert.-butyloxycarbonyl)amino ora N-tert.-butyloxycarbonylimino group, this may be converted into acorresponding amino, alkylamino or imino compound of general formula Iby treatment with an acid such as hydrochloric acid or trifluoroaceticacid.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, carboxy or imino groups may be protected during thereaction by conventional protecting groups which are cleaved again afterthe reaction.

For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

Protecting groups for an amino, alkylamino or imino group may be aformyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group,for example.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxan/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide or aprotically, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 120° C., preferablyat temperatures between 10 and 100° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0 and 100° C., but preferably at ambient temperatures between 20and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acidor by treating with iodotrimethylsilane optionally using a solvent suchas methylene chloride, dioxan, methanol or diethyl ether.

A trifluoroacetyl group is preferably cleaved by treating with an acidsuch as hydrochloric acid, optionally in the presence of a solvent suchas acetic acid at temperatures between 50 and 120° C. or by treatingwith sodium hydroxide solution, optionally in the presence of a solventsuch as tetrahydrofuran at temperatures between 0 and 50° C.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Al-linger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a (+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the saltsthereof, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids. Acids which may beused for this purpose include for example hydrochloric acid, hydrobromicacid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaricacid, succinic acid, lactic acid, citric acid, tartaric acid or maleicacid.

The compounds of general formulae II to I used as starting materials areknown from the literature in some cases or may be obtained by methodsknown from the literature (cf. Examples I to XXII) or the methodsdescribed hereinbefore, optionally with the additional use of protectinggroups (e.g. compounds of formula IV or VII and VIII).

As already mentioned hereinbefore, the compounds of general formula Iaccording to the invention and the physiologically acceptable saltsthereof have valuable pharmacological properties, particularly aninhibiting effect on signal transduction mediated by the EpidermalGrowth Factor receptor (EGF-R), whilst this may be achieved for exampleby inhibiting ligand bonding, receptor dimerisation or tyrosine kinaseitself. It is also possible that the transmission of signals tocomponents located further down is blocked.

The biological properties of the new compounds were investigated asfollows:

The inhibition of human EGF-receptor kinase was determined using thecyto-plasmic tyrosine kinase domain (methionine 664 to alanine 1186based on the sequence published in Nature 309 (1984), 418). For this theprotein was expressed in Sf9 insect cells as GST fusion protein usingthe Baculovirus expression system.

The enzyme activity was measured in the presence or absence of the testcompounds in serial dilutions. The polymer pEY (4:1) obtained from SIGMAwas used as the substrate. Biotinylated pEY (bio-pEY) was added as thetracer substrate. 100 μl of reaction solution contained 10 μl of theinhibitor in 50% DMSO, 20 μl of the substrate solution (200 mM HEPES pH7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 μg/ml bio-pEY) and20 μl of enzyme preparation. The enzyme reaction was started by theaddition of 50 μl of a 100 μM ATP solution in 10 mM of magnesiumchloride. The dilution of the enzyme preparation was adjusted so thatthe incorporation of phosphate in the bio-pEY was linear in terms oftime and quantity of enzyme. The enzyme preparation was diluted in 20 mMHEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton X-100, 1 mMDTT and 10% glycerol.

The enzyme assays were carried out at ambient temperature over a periodof 30 minutes and ended by the addition of 50 μl of a stopping solution(250 mM EDTA in 20 mM HEPES pH 7.4). 100 μl were placed on astreptavidine-coated microtitre plate and incubated for 60 minutes atambient temperature. Then the plate was washed with 200 μl of a washsolution (50 mM Tris, 0.05% Tween 20). After the addition of 100 μl ofan HRPO-labelled anti-PY antibody (PY20H Anti-PTyr:HRP made byTransduction Laboratories, 250 ng/ml) the preparation was incubated for60 minutes. Then the microtitre plate was washed three times with 200 μlof wash solution. The samples were then combined with 100 μl of aTMB-peroxidase solution (A:B=1:1, Kirkegaard Perry Laboratories). After10 minutes the reaction was stopped. The extinction was measured atOD_(450 nm) with an ELISA reader. All the results were measured threetimes.

The data were adapted by iterative calculation using an analyticalpogramme for sigmoidal curves (Graph Pad Prism Version 3.0) with avariable Hill pitch. All the iterative data produced had a correlationcoefficient of more than 0.9 and the upper and lower values of thecurves showed a spread of at least a factor of 5. The active substanceconcentration which inhibits the activity of EGF receptor kinase by 50%(IC₅₀) was derived from the curves.

The following results were obtained:

Inhibition of EGF- Compound receptor kinase (Example Nr.) IC₅₀ [nM] 1  0.13 1(1) 0.12 1(2) 2 1(3) 1.1 1(4) 0.6 1(5) 0.6 1(6) 0.69 1(7) 1.6 2  4.5 2(1) 0.16 2(2) 0.22 3   0.9 3(1) 0.14 3(2) 0.22 3(7) 0.7 3(8) 0.63(9) 0.2  3(11) 0.1  3(15) 1  3(16) 1  3(17) 0.3  3(18) 0.4  3(20) 1 3(21) 0.4 4   0.41 4(1) 0.16 7(5) 1

The compounds of general formula I according to the invention thusinhibit signal transduction by tyrosine kinases, as demonstrated by theexample of the human EGF receptor, and are therefore useful for treatingpathophysiological processes caused by hyperfunction of tyrosinekinases. These are e.g. benign or malignant tumours, particularlytumours of epithelial and neuroepithelial origin, metastasisation andthe abnormal proliferation of vascular endothelial cells(neoangiogenesis).

The compounds according to the invention are also useful for preventingand treating diseases of the airways and lungs which are accompanied byincreased or altered production of mucus caused by stimulation bytyrosine kinases, e.g. in inflammatory diseases of the airways such aschronic bronchitis, chronic obstructive bronchitis, asthma,bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cysticfibrosis, α1-antitrypsin deficiency, or coughs, pulmonary emphysema,pulmonary fibrosis and hyperreactive airways.

The compounds are also suitable for treating diseases of thegastrointestinal tract and bile duct and gall bladder which areassociated with disrupted activity of the tyrosine kinases, such as maybe found e.g. in chronic inflammatory changes such as cholecystitis,Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinaltract or such as may occur in diseases of the gastrointestinal tractwhich are associated with increased secretions, such as Ménétrier'sdisease, secreting adenomas and protein loss syndrome.

In addition, the compounds of general formula I and the physiologicallyacceptable salts thereof may be used to treat other diseases caused byabnormal function of tyrosine kinases, such as e.g. epidermalhyperproliferation (psoriasis), benign prostate hyperplasia (BPH),inflammatory processes, diseases of the immune system,hyperproliferation of haematopoietic cells, the treatment of nasalpolyps, etc.

By reason of their biological properties the compounds according to theinvention may be used on their own or in conjunction with otherpharmacologically active compounds, for example in tumour therapy, inmonotherapy or in conjunction with other anti-tumour therapeutic agents,for example in combination with topoisomerase inhibitors (e.g.etoposide), mitosis inhibitors (e.g. vinblastine), compounds whichinteract with nucleic acids (e.g. cis-platin, cyclophosphamide,adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors ofmetabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons),antibodies, etc. For treating respiratory tract diseases, thesecompounds may be used on their own or in conjunction with othertherapeutic agents for the airways, such as substances with asecretolytic (e.g. ambroxol, N-acetylcysteine), broncholytic (e.g.tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/oranti-inflammatory activity (e.g. theophylline or glucocorticoids). Fortreating diseases in the region of the gastrointestinal tract, thesecompounds may also be administered on their own or in conjunction withsubstances having an effect on motility or secretion. These combinationsmay be administered either simultaneously or sequentially.

These compounds may be administered either on their own or inconjunction with other active substances by intravenous, subcutaneous,intramuscular, intraperitoneal or intranasal route, by inhalation ortransdermally or orally, whilst aerosol formulations are particularlysuitable for inhalation.

For pharmaceutical use the compounds according to the invention aregenerally used for warm-blooded vertebrates, particularly humans, indoses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. Foradministration they are formulated with one or more conventional inertcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat orsuitable mixtures thereof in conventional galenic preparations such asplain or coated tablets, capsules, powders, suspensions, solutions,sprays or suppositories.

The following Examples are intended to illustrate the present inventionwithout restricting it:

PREPARATION OF THE STARTING COMPOUNDS Example I4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline-hydrochloride

A mixture of 10.84 g4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline and 4.50 g3-chloro-4-fluoranilin in 300 ml isopropanol is refluxed for four hoursand then left to stand overnight at ambient temperature. The precipitateformed is suction filtered, washed with isopropanol and stirred with 150ml of methanol. The suspension is stirred for another half hour atambient temperature and then suction filtered. The filter cake is washedrepeatedly with methanol and dried.

Yield: 9.07 g (60% of theory)

R_(f) value: 0.27 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (ESI⁻): m/z=478, 480 [M−H]⁻

The following compounds are obtained analogously to Example I:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline-hydrochloride

R_(f) value: 0.34 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=466, 468 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline-hydrochloride

R_(f) value: 0.17 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=469, 471 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloride

R_(f) value: 0.70 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=527, 529 [M+H]⁺

(4) 4-[(3-ethynyl-phenyl)amino]-6-acetoxy-7-methoxy-quinazoline

R_(f) value: 0.59 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=334 [M+H]⁺

(5)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(acetyloxy)-7-methoxy-quinazoline

R_(f) value: 0.20 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=466, 468 [M+H]⁺

(6)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl]amino}-6-(acetyloxy)-7-methoxy-quinazoline

The 3-methyl-4-(pyridin-3-yloxy)-aniline used (R_(f) value: 0.30 (silicagel, cyclohexane/ethyl acetate=1:1)) was prepared by reacting the sodiumsalt of 3-hydroxypyridine with 3-methyl-4-fluoro-nitrobenzene indimethylformamide and subsequently hydrogenating the3-methyl-4-(pyridin-3-yloxy)-nitrobenzene (R_(f) value: 0.58 (silicagel, cyclohexane/ethyl acetate=1:1)) in the presence of palladium onactivated charcoal.

R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=415 [M−H]⁻

Example II 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline

Prepared by reacting6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3H-quinazoline-4-on with thionylchloride in the presence of N,N-dimethylformamide in acetonitrile atreflux temperature.

R_(f) value: 0.90 (silica gel, ethyl acetate/methanol=9:1)

The following compounds are obtained analogously to Example II:

(1) 4-chloro-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline

R_(f) value: 0.85 (silica gel, ethyl acetate/methanol=9:1)

(2) 4-chloro-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline

R_(f) value: 0.92 (silica gel, ethyl acetate)

(3)4-chloro-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazolineExample III 6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3H-quinazoline-4-on

A mixture of 15.08 g2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid and 14.40 gformamidine acetate in 250 ml of absolute ethanol is refluxed overnight.The cooled reaction mixture is combined with 250 ml of water. Theprecipitate formed is suction filtered and dried at 70° C. in the dryingcupboard.

Yield: 10.00 g (65% of theory)

R_(f) value: 0.40 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=353 [M+H]⁺

The following compounds are obtained analogously to Example III:

(1) 6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-3H-quinazolin-4-one

R_(f) value: 0.60 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=339 [M+H]⁺

(2) 6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-3H-quinazolin-4-one

R_(f) value: 0.48 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=346 [M+H]⁺

(3)6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-hydroxy-3H-quinazolin-4-one

R_(f) value: 0.35 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=362 [M+H]⁺

Example IV 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid

16.40 g 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid arehydrogenated in the presence of 1.64 g Raney nickel in 800 ml ofmethanol at 55° C., until the calculated amount of hydrogen has beentaken up. The catalyst is filtered off and the filtrate evaporated down,whereupon the desired product crystallises out.

Yield: 15.08 g (100% of theory)

R_(f) value: 0.60 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

The following compounds are obtained analogously to Example IV:

(1) benzyl 2-amino-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate

R_(f) value: 0.70 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=420 [M+H]⁺

(2) 2-amino-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoicacid

R_(f) value: 0.43 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=337 [M+H]⁺

(3)2-amino-4-hydroxy-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoicacid

R_(f) value: 0.23 (silica gel, methylene chloride/methanol/aceticacid=90:10:1)

Example V 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid

Prepared by saponification of benzyl2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoate with 1 N sodiumhydroxide solution in methanol at ambient temperature.

R_(f) value: 0.20 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=374 [M+H]⁺

Example VI Benzyl2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate

42.60 g potassium-tert.-butoxide are added to 38 ml oftetrahydrofuran-4-ol in 228 ml N,N-dimethylformamide while cooling withan ice bath. The mixture is stirred for one hour at ambient temperature,then 22.90 g 6-nitro-benzo[1,3]dioxol-5-carboxylic acid are added. After1.5 hours the reaction is complete according to thin layerchromatography and 28.94 ml of benzylbromide are added dropwise whilecooling with an ice bath. The reaction mixture is stirred overnight atambient temperature, combined with 100 ml 10% citric acid and stirredfor another day at ambient temperature. Then the reaction mixture isevaporated down in vacuo at 60° C. and added to 800 ml ice water. Theaqueous phase is extracted with ethyl acetate and the combined extractsare washed with water and saturated sodium chloride solution, dried overmagnesium sulphate and evaporated.

The residue is stirred with diethyl ether, while2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acidcrystallises out as a by-product. This is filtered off and the filtrateis evaporated down. The main product remaining is benzyl2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate, which issaponified without any further purification to form carboxylic acid (seeExample V).

The following compounds are obtained analogously to Example VI:

(1) benzyl 2-nitro-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate

R_(f) value: 0.75 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

(2)2-nitro-4-hydroxy-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoicacid

No reaction is carried out with benzyl bromide.

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/aceticacid=90:10:1)

Mass spectrum (ESI⁻): m/z=381 [M−H]⁻

Example VII4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

A mixture of 410 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride,240 mg N-(tert.-butyloxycarbonyl)-2-bromo-ethylamine and 360 mgpotassium carbonate in 5 ml N,N-dimethylformamide is stirred overnightat ambient temperature. Then a further 80 mg ofN-(tert.-butyloxycarbonyl)-2-bromo-ethylamine are added and the reactionmixture is stirred for a further four hours at ambient temperature. Forworking up it is diluted with water and extracted with ethyl acetate.The combined organic phases are washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. The residue ischromatographed through a silica gel column with ethyl acetate/methanol(95:5 to 90:1) as eluant.

Yield: 370 mg (79% of theory)

R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁻): m/z=544, 546 [M−H]⁻

The following compound is obtained analogously to Example VII:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

R_(f) value: 0.38 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

Example VIII4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride

Prepared by treating4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazolinewith concentrated hydrochloric acid in dioxane at ambient temperature.

R_(f) value: 0.53 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=403, 405 [M+H]⁺

The following compounds are obtained analogously to Analog Example VIII:

(1) 6-(piperidin-4-yloxy)-3H-quinazolin-4-one×2 trifluoroacetic acid

Carried out with trifluoroacetic acid in methylene chloride.

Mass spectrum (ESI⁺): m/z=246 [M+H]⁺

(2) 6-(piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one

Carried out with trifluoroacetic acid in methylene chloride.

R_(f) value: 0.60 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=262 [M+H]⁺

Example IX4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

A solution of 7.80 ml diethyl azodicarboxylate in 100 ml methylenechloride is added dropwise to a mixture of 10.00 g4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline and9.40 g 1-(tert.-butyloxycarbonyl)-4-hydroxy-piperidine and 12.40 gtriphenylphosphine in 400 ml methylene chloride at ambient temperature.The suspension is stirred for three days at ambient temperature and thensuction filtered. The filtrate is evaporated and chromatographed througha silica gel column with methylene chloride/methanol (98:2 auf 95:5) aseluant. The crude product obtained is combined with diisopropylether,stirred overnight therein, suction filtered and dried.

Yield: 5.34 g (34% of theory)

R_(f) value: 0.46 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

Example X4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(4-bromo-butyloxy)-quinazoline

A mixture of 500 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline,165 μl 1-bromo-4-chloro-propane and 360 mg potassium carbonate in 5 mlN,N-dimethylformamide is stirred overnight at 80° C. For working up thereaction mixture is diluted with water and extracted with ethyl acetate.The combined organic phases are washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. The crudeproduct is further reacted without any more purification.

Yield: 650 mg (97% of theory)

The following compounds are obtained analogously to Example X:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-(4-bromo-butyloxy)-quinazoline

R_(f) value: 0.84 (silica gel, ethyl acetate/methanol=9:1)

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

Mass spectrum (ESI⁺): m/z=513, 515 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

R_(f) value: 0.38 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=543, 545 [M+H]⁺

Example XI 1-(2-hydroxy-ethyl)-3-methyl-tetrahydropyrimidin-2-on

Prepared by hydrogenolytically cleaving1-(2-benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-one in the presenceof palladium on activated charcoal in methanol at ambient temperature.

R_(f) value: 0.23 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=159 [M+H]⁺

Example XII 1-(2-benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-on

Prepared by reacting 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-onewith methyl iodide in the presence of potassium-tert.-butoxide inN,N-dimethylformamide at ambient temperature.

R_(f) value: 0.62 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=249 [M+H]⁺

Example XIII 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-on

Prepared by treating 1-(2-benzyloxy-ethyl)-3-(3-chloro-propyl)-urea withpotassium-tert.-butoxide in N,N-dimethylformamide at ambienttemperature.

R_(f) value: 0.42 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=235 [M+H]⁺

Example XIV 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one

Prepared by reacting 2-benzyloxy-ethylamine with3-chloro-propyl-isocyanate in tetrahydrofuran.

R_(f) value: 0.73 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=271, 273 [M+H]⁺

Example XV 3-(tert.-butyloxycarbonylamino)-cyclohexanol

Prepared by reacting 3-amino-cyclohexanol with di-tert.butylpyrocarbonate in the presence of triethylamine in a mixture ofdioxan/water (2:1) at 50° C.

R_(f) value: 0.34 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁻): m/z=214 [M−H]⁻

The following compounds are obtained analogously to Example XV:

(1) cis-4-[N-(tert.-butyloxycarbonyl)-N-methyl-amino]-cyclohexanol

The reaction takes place in methanol.

R_(f) value: 0.70 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=230 [M+H]⁺

Example XVI 6-(1-trifluoroacetyl-piperidin-4-yloxy)-3H-quinazolin-4-one

Prepared by reacting 6-(piperidin-4-yloxy)-3H-quinazolin-4-one×2trifluoroacetic acid with trifluoroacetic acid anhydride in the presenceof triethylamine in tetrahydrofuran.

R_(f) value: 0.48 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=342 [M+H]⁺

The following compounds are obtained analogously to Example XVI:

(1)6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one

Carried out with methyl trifluoroacetate in the presence of Hünig basein methanol.

R_(f) value: 0.80 (silica gel, methylene chloride/methanol=4:1)

Mass spectrum (ESI⁺): m/z=358 [M+H]⁺

Example XVII2-nitro-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid

21.00 g potassium-tert.-butoxide are added batchwise to 25.14 g1-(tert.-butyloxycarbonyl)-piperidin-4-ol in 120 mlN,N-dimethylformamide while cooling with an ice bath, while thetemperature is kept below 10° C. The mixture is stirred for a further 30minutes while cooling with an ice bath, then 11.60 g of5-fluoro-2-nitro-benzoic acid are added. After another three hours thereaction mixture is poured onto water, adjusted to pH 1 with conc.hydrochloric acid and extracted with ethyl acetate. The combined organicphases are washed with dilute citric acid solution, dried over magnesiumsulphate and evaporated. The residue is triturated with diethyl ether,suction filtered and dried. More product crystallises out of thefiltrate after standing for some time, and this is also suction filteredand dried.

Yield: 9.58 g (42% of theory)

R_(f) value: 0.43 (silica gel, methylene chloride/methanol/aceticacid=90:10:1)

Mass spectrum (ESI⁺): m/z=367[M+H]⁺

Example XVIII4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-bromacetyl-piperidin-4-yloxy)-quinazolineand4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloracetyl-piperidin-4-yloxy)-quinazoline

Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazolinewith bromoacetic acid chloride in the presence of Hünig base intetrahydrofuran at ambient temperature. A mixture of the bromine andchlorine compounds is obtained.

R_(f) value: 0.43 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=493, 495, 497 [M+H]⁺ and 449, 451, 453 [M+H]⁺

The following compounds are obtained analogously to Example XVIII:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloracetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

The reaction takes place with chloroacetyl chloride.

R_(f) value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁻): m/z=477, 479, 481 [M−H]⁻

Example XIX1-methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1-ium-iodide

Prepared by reacting 3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazole withmethyl iodide in acetonitrile at ambient temperature. The crude productis reacted further without any more purification.

The following compounds are obtained analogously to Example XIX:

(1)1-methyl-3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-ium-iodide

R_(f) value: 0.12 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(2)1-methyl-3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-ium-iodide

R_(f) value: 0.02 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(3)1-methyl-3-[(S,S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-3H-imidazol-1-ium-iodide

R_(f) value: 0.01 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(4)1-methyl-3-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-3H-imidazol-1-ium-iodide

R_(f) value: 0.03 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(5)1-methyl-3-[(N-methyl-N-3-methoxypropyl-amino)carbonyl]-3H-imidazol-1-ium-iodide

R_(f) value: 0.12 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Example XX 3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazole

Prepared by reacting [1,4]oxazepan with N,N′-carbonyldiimidazole in thepresence of triethylamine in tetrahydrofuran at ambient temperature.

R_(f) value: 0.30 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=196 [M+H]⁺

The following compounds are obtained analogously to Example XX:

(1) 3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazole

R_(f) value: 0.46 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(2) 3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazole

R_(f) value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(3) 3-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-3H-imidazole

R_(f) value: 0.59 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

(4) 3-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-3H-imidazole

R_(f) value: 0.32 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(5) 3-[(N-methyl-N-3-methoxypropyl-amino)carbonyl]-3H-imidazole

R_(f) value: 0.36 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Example XXI4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-quinazoline

Prepared by treating4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloridewith saturated sodium hydrogen carbonate solution in methanol at ambienttemperature. In addition to the desired product, some4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-hydroxy-quinazolineis also isolated as a by-product.

R_(f) value: 0.20 (silica gel, methylene chloride/methanol=20:1)

Mass spectrum (ESI⁻): m/z=483, 485 [M−H]⁻

The following compounds are obtained analogously to Example XXI:

(1) 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline

Carried out with 40% sodium hydroxide solution in ethanol.

R_(f) value: 0.32 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=292 [M+H]⁺

(2)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-hydroxy-7-methoxy-quinazoline

R_(f) value: 0.70 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁻): m/z=424, 426 [M−H]⁻

(3)4-{[3-methyl-4-(pyridin-3-yloxy)phenyl}amino)-6-hydroxy-7-methoxy-quinazoline

R_(f) value: 0.23 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁻): m/z=373 [M−H]⁻

Example XXII6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-3H-quinazolin-4-one

Prepared by reacting6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-onewith acetic anhydride in pyridine at 80° C.

R_(f) value: 0.60 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=400 [M+H]⁺

Example XXIII4-[(3-Chloro-4-fluorophenyl)amino]-6-{1-[(4-nitrophenyloxy)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Prepared by reacting4-[(3-chloro-4-fluorophenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline(Example 2(2)) with (4-nitrophenyl) chloroformate.

R_(f) value: 0.48 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Preparation of the End Compounds Example 14-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline

300 mg of4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6ml acetonitrile are combined with 114 μl (R)-3-hydroxy-tetrahydrofuranand 370 mg triphenylphosphine. Then 234 μl diethyl azodicarboxylate areadded and the reaction mixture is stirred overnight at ambienttemperature. For working up the reaction mixture is filtered and thefiltrate evaporated down in vacuo. The crude product is purified bychromatography over a silica gel column with ethyl acetate/-methanol(95:5) as eluant.

Yield: 53 mg (15% of theory)

melting point: 178° C.

Mass spectrum (ESI⁺): m/z=390, 392 [M+H]⁺

The following compounds are obtained analogously to Example 1:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.54 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=404, 406 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

R_(f) value: 0.70 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.64 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=390, 392 [M+H]⁺

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

R_(f) value: 0.65 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

melting point: 184° C.

Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

(6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.52 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=404, 406 [M+H]⁺

(7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

melting point: 218° C.

Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

(8)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert.-butyloxycarbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazoline

Carried out with diisopropyl azodicarboxylate in methylene chloride.

R_(f) value: 0.51 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

(9)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-3-yloxy]-7-methoxy-quinazoline

Carried out with diisopropyl azodicarboxylate in methylene chloride.

R_(f) value: 0.56 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁻): m/z=501, 503 [M−H]⁻

(10)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethoxy]-quinazoline

Carried out with diisopropyl azodicarboxylate in methylene chloride.

melting point: 235° C.

Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

(11)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

Carried out with diisopropyl azodicarboxylate in methylene chloride.

R_(f) value: 0.68 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁻): m/z=515, 517 [M−H]⁻

(12)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(tert.-butyloxycarbonyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Carried out with diisopropyl azodicarboxylate in methylene chloride.

R_(f) value: 0.37 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=531, 533 [M+H]⁺

(13)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[N-(tert.-butyloxycarbonyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Carried out with diisopropyl azodicarboxylate in methylene chloride.

melting point: 231° C.

Mass spectrum (ESI⁺): m/z=531, 533 [M+H]⁺

Example 24-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline×trifluoroaceticacid

Prepared by treating4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazolinewith trifluoroacetic acid in methylene chloride at ambient temperature.

melting point: 221° C.

Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

The following compounds are obtained analogously to Example 2:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline×trifluoroaceticacid

melting point: 232° C.

Mass spectrum (ESI⁺): m/z=403, 405 [M+H]⁺

Example 34-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline×trifluoroaceticacid with methanesulphonic acid chloride in the presence of Hünig basein tetrahydrofuran at ambient temperature.

R_(f) value: 0.77 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=40:10:1)

Mass spectrum (ESI⁺): m/z=495, 497 [M+H]⁺

The following compounds are obtained analogously to Example 3:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.20 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=495, 497 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=481, 483 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloro-propyl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with 3-chloropropansulphonyl chloride.

R_(f) value: 0.79 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁻): m/z=555, 557, 559 [M−H]⁻

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(3-chloro-propyl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with 3-chloropropanesulphonyl chloride.

R_(f) value: 0.42 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=557, 559, 561 [M+H]⁺

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

The reaction takes place with acetic anhydride.

melting point: 216° C.

Mass spectrum (ESI⁺): m/z=445, 447 [M+H]⁺

(6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with N,N-dimethylcarbamoylchloride.

R_(f) value: 0.28 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=474, 476 [M+H]⁺

(7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride inacetonitrile.

R_(f) value: 0.37 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

(8)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with methoxyacetic acid chloride.

R_(f) value: 0.80 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=475, 477 [M+H]⁺

(9)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline

The reaction takes place with bromocyanogen in methylene chloride.

R_(f) value: 0.40 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=428, 430 [M+H]⁺

(10)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)sulphonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

R_(f) value: 0.24 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=510, 512 [M+H]⁺

(11)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulphonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)sulphonyl chloride inacetonitrile.

R_(f) value: 0.29 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=552, 554 [M+H]⁺

(12)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-3-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=481, 483 [M+H]⁺

(13)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-1-methanesulphonyl-pyrrolidin-3-yloxy)-7-methoxy-quinazoline

melting point: 249° C.

Mass spectrum (ESI⁺): m/z=467, 469 [M+H]⁺

(14)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methanesulphonylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

R_(f) value: 0.49 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=524, 526 [M+H]⁺

(15)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

The reaction takes place with acetic anhydride.

R_(f) value: 0.51 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

(16)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

R_(f) value: 0.69 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=524, 526 [M+H]⁺

(17)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride inacetonitrile.

R_(f) value: 0.38 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

(18)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)sulphonyl chloride inacetonitrile.

melting point: 237° C.

Mass spectrum (ESI⁻): m/z=564, 566 [M−H]⁻

(19)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.66 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁻): m/z=493, 495 [M−H]⁻

(20)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline

The reaction takes place with acetylchloride in acetonitrile.

melting point: 224° C.

Mass spectrum (ESI⁺): m/z=475, 477 [M+H]⁺

(21)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline

melting point: 227° C.

Mass spectrum (ESI⁺): m/z=511, 513 [M+H]⁺

(22)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-3-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with acetylchloride in acetonitrile. Cis- andtrans-isomer are separated by chromatography over a silica gel column.

R_(f) value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

(23)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-3-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with acetylchloride in acetonitrile. Cis- andtrans-isomer are separated by chromatography over a silica gel column.

R_(f) value: 0.49 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

(24)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-acetylamino-propyloxy)-quinazoline

The reaction takes place with acetylchloride.

melting point: 225° C.

Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

(25)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-methanesulphonylamino-propyloxy)-quinazoline

melting point: 222° C.

Mass spectrum (ESI⁺): m/z=525, 527 [M+H]⁺

(26)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-quinazoline

R_(f) value: 0.44 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=451, 453 [M+H]⁺

(27)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride inacetonitrile.

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=486, 488 [M+H]⁺

(28)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-quinazoline

The reaction takes place with acetic anhydride.

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=415, 417 [M+H]⁺

(29)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yloxy}-quinazoline

The reaction takes place with N,N-dimethylcarbamoylchloride.

R_(f) value: 0.47 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=444, 446 [M+H]⁺

(30)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-acetylamino-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with acetic anhydride.

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

(31)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with N,N-dimethylcarbamoylchloride.

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

(32)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

The reaction takes place with methoxyacetic acid chloride.

R_(f) value: 0.35 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

(33)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-quinazoline

The reaction takes place with methoxyacetic acid chloride.

R_(f) value: 0.41 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=445, 447 [M+H]⁺

(34)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

The reaction takes place with isopropyl chloroformate.

R_(f) value: 0.67 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=98:2:1)

Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

(35)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-quinazoline

The reaction takes place with bromocyanogen in methylene chloride.

R_(f) value: 0.49 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁻): m/z=396, 398 [M−H]⁻

(36)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)sulphonyl]-piperidin-4-yloxy}-quinazoline

The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

R_(f) value: 0.34 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=480, 482 [M+H]⁺

(37)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulphonyl]-piperidin-4-yloxy}-quinazoline

The reaction takes place with (morpholin-4-yl)sulphonyl chloride inacetonitrile.

R_(f) value: 0.15 (silica gel, cyclohexane/ethyl acetate=1:1)

Mass spectrum (ESI⁺): m/z=522, 524 [M+H]⁺

(38)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-quinazoline

The reaction takes place with acetic anhydride in acetonitrile.

melting point: 221° C.

Mass spectrum (ESI⁺): m/z=458, 460 [M+H]⁺

(39)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(diethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with N,N-diethylcarbamoylchloride.

R_(f) value: 0.40 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=95:5:1)

Mass spectrum (ESI⁺): m/z=502, 504 [M+H]⁺

(40)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with (piperidin-1-yl)carbonylchloride.

R_(f) value: 0.51 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=95:5:1)

Mass spectrum (ESI⁻): m/z=512, 514 [M−H]⁻

(41)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(pyrrolidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with (pyrrolidin-1-yl)carbonylchloride.

melting point: 237° C.

Mass spectrum (ESI⁺): m/z=500, 502 [M+H]⁺

(42)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(4-methyl-piperazin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with(4-methyl-piperazin-1-yl)carbonylchloride-hydrochloride.

R_(f) value: 0.28 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁻): m/z=527, 529 [M−H]⁻

(43)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

The reaction takes place in methylene chloride.

R_(f) value: 0.71 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=509, 511 [M+H]⁺

(44)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

The reaction takes place with acetic anhydride.

melting point: 234° C.

Mass spectrum (ESI⁺): m/z=473, 475 [M+H]⁺

(45)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with methoxyacetic acid chloride.

R_(f) value: 0.40 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

(46)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

The reaction takes place with N,N-dimethylcarbamoylchloride.

R_(f) value: 0.51 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=502, 504 [M+H]⁺

(47)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride.

R_(f) value: 0.50 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=544, 546 [M+H]⁺

(48)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)sulphonyl chloride inacetonitrile.

R_(f) value: 0.24 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=580, 582 [M+H]⁺

(49)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminosulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

R_(f) value: 0.53 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=538, 540 [M+H]⁺

(50)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with ethanesulphonic acid chloride in methylenechloride.

R_(f) value: 0.41 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=509, 511 [M+H]⁺

(51)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-ethoxy-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride.

R_(f) value: 0.48 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

(52)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=495, 497 [M+H]⁺

(53)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-ethoxy-quinazoline

The reaction takes place with methoxyacetic acid chloride.

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=20:1)

Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

(54)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

R_(f) value: 0.47 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=525, 527 [M+H]⁺

(55)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride.

R_(f) value: 0.48 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=560, 562 [M+H]⁺

(56)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline

The reaction takes place with methoxyacetic acid chloride.

R_(f) value: 0.48 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=519, 521 [M+H]⁺

(57)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with acetic anhydride.

melting point: 281° C.

Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

(58)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

The reaction takes place with methoxyacetic acid chloride.

melting point: 264° C.

Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

(59)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with (piperidin-1-yl)carbonylchloride.

melting point: 253° C.

Mass spectrum (ESI⁺): m/z=542, 544 [M+H]⁺

(60)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with(4-methyl-piperazin-1-yl)carbonylchloride-hydrochloride.

melting point: 262° C.

Mass spectrum (ESI⁺): m/z=557, 559 [M+H]⁺

(61)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-ethanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

The reaction takes place with ethanesulphonic acid chloride in methylenechloride.

R_(f) value: 0.19 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=523, 525 [M+H]⁺

(62)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride.

R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

(63)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)sulphonyl chloride inacetonitrile.

R_(f) value: 0.81 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=566, 568 [M+H]⁺

(64)4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

The reaction takes place with acetic anhydride.

R_(f) value: 0.30 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=417 [M+H]⁺

(65)4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

The reaction takes place with methoxyacetic acid chloride.

R_(f) value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=447 [M+H]⁺

(66)4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.59 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=453 [M+H]⁺

(67)4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride.

R_(f) value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=488 [M+H]⁺

(68)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=509, 511 [M+H]⁺

(69)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The reaction takes place with (morpholin-4-yl)carbonylchloride.

R_(f) value: 0.54 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=544, 546 [M+H]⁺

(70)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl]amino)-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-methanesulphonate

R_(f) value: 0.58 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=536 [M+H]⁺

(71)4-[(3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.80 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=587, 589 [M+H]⁺

Example 44-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

23 μl of morpholine are added to 60 mg of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloro-propyl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazolinein 2 ml acetonitrile and the reaction mixture is refluxed overnight. Forworking up the mixture is taken up in ethyl acetate and washed withwater. The organic phase is dried over magnesium sulphate and evaporateddown. The crude product is purified through a silica gel column withmethylene chloride/methanol (9:1) as eluant.

Yield: 18 mg (27% of theory)

R_(f) value: 0.36 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=608, 610 [M+H]⁺

The following compounds are obtained analogously to Example 4:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.16 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=608, 610 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]-quinazoline

Carried out in the presence of sodium carbonate and sodium iodide inN-methylpyrrolidone at 100° C.

R_(f) value: 0.18 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=40:10:0.5)

Mass spectrum (ESI⁺): m/z=531, 533 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]-quinazoline

Carried out in the presence of sodium carbonate and sodium iodide inN-methylpyrrolidone at 100° C.

R_(f) value: 0.32 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=80:20:1)

Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)acetyl]-piperidin-4-yloxy}-quinazoline

Carried out in the presence of Hünig base in tetrahydrofuran at ambienttemperature.

R_(f) value: 0.30 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=500, 502 [M+H]⁺

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin-4-yloxy)-quinazoline

Carried out in the presence of Hünig base in tetrahydrofuran at ambienttemperature.

R_(f) value: 0.11 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=458, 460 [M+H]⁺

(6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

Carried out in the presence of Hünig base in tetrahydrofuran at ambienttemperature.

R_(f) value: 0.19 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

(7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)acetyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Carried out in the presence of Hünig base in tetrahydrofuran at ambienttemperature.

Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

Example 54-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-pyrrolidin-3-yloxy)-7-methoxy-quinazoline-dihydrochloride

A solution of 370 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert.-butyloxy-carbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazolinein 5 ml dioxane is combined with 0.32 ml concentrated hydrochloric acidand stirred overnight at ambient temperature. The precipitate formed issuction filtered and washed with copious amounts of dioxane. The crudeproduct is dissolved in a little methanol and re-precipitated by theaddition of the same amount of ethyl acetate. The white solid thusobtained is suction filtered and dried.

Yield: 200 mg (57% of theory)

melting point: 281° C.

Mass spectrum (ESI⁺): m/z=389, 391 [M+H]⁺

The following compounds are obtained analogously to Example 5:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-dihydrochloride

melting point: 263° C.

Mass spectrum (ESI⁺): m/z=403, 505 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-dihydrochloride

melting point: 277° C.

Mass spectrum (ESI⁺): m/z=446, 448 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-amino-ethoxy)-quinazoline-dihydrochloride

Carried out with isopropanolic hydrochloric acid (5-6 M) in methylenechloride.

R_(f) value: 0.58 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=433, 435 [M+H]⁺

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-amino-propyloxy)-quinazoline-dihydrochloride

Carried out with isopropanolic hydrochloric acid (5-6 M) in methylenechloride.

R_(f) value: 0.44 (Reversed phase ready-made TLC plate (E. Merck),methanol/5% aqueous sodium chloride solution=7:3)

Mass spectrum (ESI⁺): m/z=447, 449 [M+H]⁺

(6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-quinazoline-dihydrochloride

R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=416, 418 [M+H]⁺

(7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

Carried out with isopropanolic hydrochloric acid (5-6 M) in methylenechloride.

R_(f) value: 0.35 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

(8)4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride

Carried out with isopropanolic hydrochloric acid (5-6 M) in methylenechloride.

R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=375 [M+H]⁺

(9)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

melting point: 251° C.

Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

(10)4-{([3-methyl-4-(pyridin-3-yloxy)-phenyl]amino)-6-(piperidin-4-yloxy)-7-methoxy-quinazolinedihydrochloride

R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=458 [M+H]⁺

(11)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(piperidin-4-yloxy)-7-methoxy-quinazolinedihydrochloride

R_(f) value: 0.38 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=507, 509 [M−H]⁻

(12)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl]amino)-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxy-quinazolinedihydrochloride

R_(f) value: 0.58 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=472 [M+H]⁺

(13)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxy-quinazolinedihydrochloride

R_(f) value: 0.48 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=523, 525 [M+H]⁺

Example 64-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline

A mixture of 9.00 g4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline-hydrochlorideand 50 ml trifluoroacetic acid is heated to 100° C. for 1.5 hours. Thenthe reaction mixture is evaporated and the residue is taken up in 10 mlacetonitrile. This solution is added dropwise to 100 ml saturated sodiumhydrogen carbonate solution with vigorous stirring. After 1.5 hours theprecipitate formed is suction filtered and washed several times withwater. The crude product is stirred with diethyl ether, suction filteredand dried.

Yield: 5.90 g (87% of theory)

R_(f) value: 0.21 (silica gel, ethyl acetate)

Mass spectrum (ESI⁺): m/z=390, 392 [M+H]⁺

The following compounds are obtained analogously to Example 6:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline

R_(f) value: 0.44 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=376, 378 [M+H]⁺

Example 74-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3-(morpholin-4-yl)-propyloxy]-quinazoline

A mixture of 300 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline,130 mg 3-(morpholin-4-yl)-propylchloride and 530 mg potassium carbonatein 5 ml N,N-dimethylformamide is stirred overnight at 80° C. For workingup the reaction mixture is diluted with 25 ml of water and extractedwith ethyl acetate. The combined organic phases are washed withsaturated sodium chloride solution, dried over magnesium sulphate andevaporated. The residue is stirred with diethyl ether, suction filteredand dried.

Yield: 250 mg (63% of theory)

melting point: 205° C.

Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

The following compounds are obtained analogously to Example 7:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(morpholin-4-yl)-ethoxy]-quinazoline

R_(f) value: 0.33 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=40:10:0.5)

Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline

R_(f) value: 0.76 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=418, 420 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[3-(morpholin-4-yl)-propyloxy]-quinazoline

R_(f) value: 0.20 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁻): m/z=501, 503[M−H]⁻

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2-(morpholin-4-yl)-ethoxy]-quinazoline

R_(f) value: 0.19 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

R_(f) value: 0.57 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=448, 450 [M+H]⁺

(6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(tert.-butyloxycarbonylamino)-ethoxy]-quinazoline

R_(f) value: 0.64 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=95:5:0.1)

Mass spectrum (ESI⁺): m/z=533, 535 [M+H]⁺

(7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3-(tert.-butyloxycarbonylamino)-propyloxy]-quinazoline

R_(f) value: 0.74 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=95:5:0.1)

Mass spectrum (ESI⁺): m/z=547, 549 [M+H]⁺

Example 84-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazoline

A solution of 4.55 g4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline-hydrochloridein 35 ml methanol is combined with 13 ml (3 N) sodium hydroxide solutionand stirred for about half an hour at ambient temperature. For workingup the reaction mixture is diluted with water and extracted with ethylacetate. The combined organic phases are washed with saturated sodiumchloride solution, dried over magnesium sulphate and evaporated. Theresidue is stirred with diethyl ether, suction filtered and dried.

Yield: 3.00 g (89% of theory)

R_(f) value: 0.48 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=373, 375 [M+H]⁺

The following compounds are obtained analogously to Example 8:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxy-quinazoline

R_(f) value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

R_(f) value: 0.10 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=447, 449 [M+H]⁺

Example 94-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(ethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazolinewith ethyl isocyanate in tetrahydrofuran at ambient temperature.

R_(f) value: 0.53 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=474, 476 [M+H]⁺

The following compounds are obtained analogously to Example 9:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(isopropylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

melting point: 236° C.

Mass spectrum (ESI⁻): m/z=486, 488 [M−H]⁻

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(phenylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

R_(f) value: 0.70 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=95:5:0.1)

Mass spectrum (ESI⁺): m/z=522, 524 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(ethylamino)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.38 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=502, 504 [M+H]⁺

Example 104-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yloxy}-quinazoline

Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazolinewith 2-chloro-N,N-dimethylacetamide in the presence of potassiumcarbonate in N,N-dimethylformamide at ambient temperature.

R_(f) value: 0.24 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=458, 460 [M+H]⁺

The following compounds are obtained analogously to Example 10:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yloxy}-quinazoline

R_(f) value: 0.42 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=500, 502 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline

melting point: 251° C.

Mass spectrum (ESI⁺): m/z=460, 462 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

melting point: 233° C.

Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

melting point: 245° C.

Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxyethyl)-piperidin-4-yloxy}-7-methoxy-quinazoline

melting point: 178° C.

Mass spectrum (ESI⁺): m/z=461, 463 [M+H]⁺

(6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

melting point: 234° C.

R_(f) value: 0.28 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=514, 516 [M+H]⁺

Example 114-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(tetrahydropyran-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

90 mg 1-hydroxy-1H-benzotriazole and 250 mg2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborateare added to a mixture of 300 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride,82 mg tetrahydropyran-4-carboxylic acid and 0.54 ml Hünig base in 5 mlN,N-dimethylformamide. The reaction mixture is stirred overnight atambient temperature. For working up it is combined with 25 ml ethylacetate and washed with water, 10% potassium carbonate solution andsaturated sodium chloride solution. The organic phase is dried overmagnesium sulphate and evaporated. The residue is stirred with a littleethyl acetate, suction filtered and dried.

Yield: 250 mg (77% of theory)

R_(f) value: 0.43 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=515, 517 [M+H]⁺

The following compounds are obtained analogously to Example 11:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(tetrahydropyran-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

R_(f) value: 0.44 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=529, 531 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.31 (silica gel, ethyl acetate/methanol=9:1)

Mass spectrum (ESI⁺): m/z=543, 545 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(R)-(tetrahydrofuran-2-yl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

Melting point: 243° C.

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S)-(tetrahydrofuran-2-yl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.34 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.31 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=487, 489 [M−H]⁻

Example 124-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[([1,4]oxazepan-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochlorideand 1.05 ml triethylamine are added to 900 mg of1-methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1-ium-iodide in 10ml methylene chloride. The yellowish suspension is stirred for about 24hours at ambient temperature. For working up the reaction mixture iscombined with 50 ml methylene chloride and extracted with water as wellas 10% citric acid. The organic phase is washed with saturated sodiumchloride solution, dried over magnesium sulphate and evaporated down.The residue is chromatographed through a silica gel column withmethylene chloride/methanol/conc. ammonia as eluant. The desired productis stirred with diethyl ether, suction filtered and dried.

Yield: 800 mg (80% of theory)

R_(f) value: 0.30 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

The following compounds are obtained analogously to Example 12:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

R_(f) value: 0.41 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=544, 546 [M+H]⁺

(2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

R_(f) value: 0.50 (silica gel, ethyl acetate/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

Melting point: 193° C.

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

Melting point: 171° C.

(5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-3-methoxypropyl-amino)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.23 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=532, 534 [M+H]⁺

Example 134-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

35 μl 37% aqueous formalin solution and 110 mg of sodiumtriacetoxyborohydride are added to 175 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxy-quinazolinein 1 ml of tetrahydrofuran. The reaction mixture is stirred for aboutfour hours at ambient temperature. For working up 5 ml saturated sodiumhydrogen carbonate solution are added and the mixture is stirredthoroughly. Then 20 ml ethyl acetate are added and the aqueous phase isseparated off. The organic phase is washed with water and saturatedsodium chloride solution, dried over magnesium sulphate and evaporated.The residue is stirred with diisopropylether, suction filtered anddried.

Yield: 144 mg (80% of theory)

R_(f) value: 0.80 (silica gel, methylene chloride/methanol/conc. aqueousammonia=60:10:1)

Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

The following compounds are obtained analogously to Example 13:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline

R_(f) value: 0.85 (silica gel, methylene chloride/methanol/conc. aqueousammonia=60:10:1)

Mass spectrum (ESI⁺): m/z=461, 463 [M+H]⁺

(2)4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-hydrochloride

R_(f) value: 0.26 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=389 [M+H]⁺

(3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.80 (aluminium oxide, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=445, 447 [M+H]⁺

(4)4-[(3-chloro-4-fluoro-phenyl)amino]-S-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazolinehydrochloride

Carried out with acetaldehyde

R_(f) value: 0.44 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

(5)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.68 (silica gel, methylene chloride/methanol/conc. aqueousammonia=60:10:1)

Mass spectrum (ESI⁺): m/z=472 [M+H]⁺

(6)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.70 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=523, 525 [M+H]⁺

Example 144-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

A mixture of 3.00 g4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline, 4.50 g1-(tert.-butyloxycarbonyl)-4-(p-toluolsulphonyloxy)-piperidin and 2.90 gpotassium carbonate in 30 ml N,N-dimethylformamide is stirred for twodays at 60° C. For working up the mixture is combined with 200 ml ethylacetate and extracted with water. The organic phase is washed withsaturated sodium chloride solution, dried over magnesium sulphate andevaporated. The crude product is purified over a silica gel column withmethylene chloride/methanol/conc. ammonia as eluant.

Yield: 3.25 g (67% of theory)

R_(f) value: 0.25 (silica gel, methylene chloride/methanol/conc. aqueousammonia=95:5:1)

Mass spectrum (ESI⁺): m/z=475 [M+H]⁺

The following compounds are obtained analogously to Example 14:

(1)4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=376 [M+H]⁺

(2)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline

R_(f) value: 0.32 (silica gel, methylene chloride/methanol=20:1)

Mass spectrum (ESI⁺): m/z=510, 512 [M+H]⁺

(3)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline

R_(f) value: 0.55 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=459 [M+H]⁺

(4)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-(1-tert.butyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=558 [M+H]⁺

(5)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl)amino}-6-(1-tert.butyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

R_(f) value: 0.65 (silica gel, methylene chloride/methanol=9:1)

Mass spectrum (ESI⁺): m/z=609, 611 [M+H]⁺

(6)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-[trans-4-(tert.butyloxycarbonylamino)-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The alkylating agent used,cis-4-(tert.butyloxycarbonylamino)-1-(4-methylphenylsulphonyloxy)-cyclohexane(mass spectrum (ESI⁺): m/z=370 [M+H]⁺) was prepared by reactingcis-4-(tert.butyloxycarbonylamino)-cyclohexanol with4-methylphenyl-sulphonyl chloride in pyridine.

Mass spectrum (ESI⁺): m/z=572 [M+H]⁺

(7)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-[trans-4-(tert.butyloxycarbonylamino)-cyclohexan-1-yloxy)-7-methoxy-quinazoline

The alkylating agent used,cis-4-(tert.butyloxycarbonylamino)-1-(4-methylphenylsulphonyloxy)-cyclohexane(mass spectrum (ESI⁺): m/z=370 [M+H]⁺) was prepared by reactingcis-4-(tert.butyloxycarbonylamino)-cyclohexanol with4-methylphenyl-sulphonyl chloride in pyridine.

Mass spectrum (ESI⁺): m/z=623, 625 [M+H]⁺

Example 154-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

A mixture of 410 mg of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride,240 mg of N-(tert.-butyloxycarbonyl)-2-bromo-ethylamine and 360 mg ofpotassium carbonate in 5 ml N,N-dimethylformamide is stirred overnightat ambient temperature. Then another 80 mgN-(tert.-butyloxycarbonyl)-2-bromo-ethylamine are added and the reactionmixture is stirred for a further four hours at ambient temperature. Forworking up it is diluted with water and extracted with ethyl acetate.The combined organic phases are washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. The residue ischromatographed through a silica gel column with ethyl acetate/methanol(95:5 to 90:1) as eluant.

Yield: 370 mg (79% of theory)

R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁻): m/z=544, 546 [M−H]⁻

The following compound is obtained analogously to Example 15:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

R_(f) value: 0.38 (Reversed phase ready-made TLC plate (E. Merck),acetonitrile/water/trifluoroacetic acid=50:50:1)

Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

Example 164-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(4-nitrophenyloxy)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazolinewith 3-methoxypropylamine at 60° C.

R_(f) value: 0.33 (silica gel, methylene chloride/methanol/conc. aqueousammonia=90:10:1)

Mass spectrum (ESI⁺): m/z=518, 520 [M+H]⁺

The following compound is obtained analogously to Example 15:

(1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Mass spectrum (ESI⁺): m/z=504, 506 [M+H]⁺

The following compounds may also be prepared analogously to theforegoing Examples and other methods known from the literature:

Example No. Structure  (1)

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(186)

Example 16 Coated Tablets Containing 75 mg of Active Substance

1 tablet core contains:

active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mgpolyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mgmagnesium stearate  1.5 mg 230.0 mg 

Preparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks 13 mm in diameter areproduced in a tablet-making machine and these are then rubbed through ascreen with a mesh size of 1.5 mm using a suitable machine and mixedwith the rest of the magnesium stearate. This granulate is compressed ina tablet-making machine to form tablets of the desired shape.

-   -   Weight of core: 230 mg    -   die: 9 mm, convex

The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax.

-   -   Weight of coated tablet: 245 mg.

Example 17 Tablets Containing 100 mg of Active Substance Composition:

1 tablet contains:

active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mgpolyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Method of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Diameter: 10 mm, biplanar, facetted on both sides and notched on        one side.

Example 18 Tablets Containing 150 mg of Active Substance Composition:

1 tablet contains:

active substance 50.0 mg powdered lactose 89.0 mg corn starch 40.0 mgcolloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg 

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

-   -   Weight of tablet: 300 mg    -   die: 10 mm, flat

Example 19 Hard Gelatine Capsules Containing 150 mg of Active Substance

1 capsule contains:

active substance 50.0 mg corn starch (dried) approx. 80.0 mg lactose(powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules.

-   -   Capsule filling: approx. 320 mg    -   Capsule shell: size 1 hard gelatine capsule.

Example 20 Suppositories Containing 150 mg of Active Substance

1 suppository contains:

active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2000.0 mg 

Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmoulds.

Example 21 Suspension Containing 50 mg of Active Substance

100 ml of suspension contain:

active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methylp-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 gglycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist.water 100 ml

Preparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

-   -   5 ml of suspension contain 50 mg of active substance.

Example 22 Ampoules Containing 10 mg Active Substance Composition:

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater  2.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

Example 23 Ampoules Containing 50 mg of Active Substance Composition:

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

Example 24 Capsules for Powder Inhalation Containing 5 mg of ActiveSubstance

1 capsule contains:

active substance 5.0 mg lactose for inhalation 15.0 mg 20.0 mg

Preparation:

The active substance is mixed with lactose for inhalation. The mixtureis packed into capsules in a capsule-making machine (weight of the emptycapsule approx. 50 mg).

-   -   weight of capsule: 70.0 mg    -   size of capsule=3

Example 25 Inhalable Solution for Hand-Held Nebulisers Containing 2.5 mgActive Substance

1 spray contains:

active substance 2.500 mg benzalkonium chloride 0.001 mg 1N hydrochloricacid q.s. ethanol/water (50/50) 15.000 mg 

Preparation:

The active substance and benzalkonium chloride are dissolved inethanol/water (50/50). The pH of the solution is adjusted with 1Nhydrochloric acid. The resulting solution is filtered and transferredinto suitable containers for use in hand-held nebulisers (cartridges).

-   -   Contents of the container: 4.5 g

1. A method of treating inflammatory diseases of the airways selectedfrom the group consisting of chronic bronchitis, chronic obstructivebronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis orsinusitis, cystic fibrosis, alpha1-antitrypsin deficiency, coughs,pulmonary emphysema, pulmonary fibrosis and hyperreactive airways, saidmethod comprising administering to a patient in need of such treatmentan effective amount of a compound selected from the group consisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminosulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-ethoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-ethoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline

4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl]amino)-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-methanesulphonate

4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline

and4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline

and the pharmaceutically acceptable salts thereof.
 2. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 3. The methodaccording to claim 1 wherein the inflammatory disease of the airways isselected from the group consisting of chronic bronchitis and chronicobstructive bronchitis.
 4. The method according to claim 3 wherein thecompound is selected from the group consisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 5. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 6. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 7. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 8. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 9. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 10. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 11. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminosulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 12. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminosulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 13. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 14. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 15. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 16. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 17. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 18. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 19. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-ethoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 20. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-ethoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 21. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-ethoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 22. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-ethoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 23. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,and the pharmaceutically acceptable salts thereof.
 24. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,and the pharmaceutically acceptable salts thereof.
 25. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,and the pharmaceutically acceptable salts thereof.
 26. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,and the pharmaceutically acceptable salts thereof.
 27. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,and the pharmaceutically acceptable salts thereof.
 28. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,and the pharmaceutically acceptable salts thereof.
 29. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 30. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 31. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 32. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-{N-methanesulphonyl-N-methyl-amino}-cyclohexan-1-yloxy]-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 33. The methodaccording to claim 1 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.
 34. The methodaccording to claim 3 wherein the compound is selected from the groupconsisting of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,and the pharmaceutically acceptable salts thereof.